The [2.2.2]-diazabicyclic ring skeleton is shared among a number of prenylated indole alkaloids including the brevianamides, paraherquamides, stephacidins, notamides, and malbrancheamides (see FIG. 1, and see also Williams, R. M. Chem. Pharm. Bull., 2002, 50, 711-740; Williams, R. M.; Cox, R. J. Acc. Chem. Res. 2003, 36 (2), 127-139). These fungal-derived natural products possess a wide spectrum of biological activities including antitumor, antihelmintic, antibacterial, calmodulin inhibition, and insecticidal properties, see Qian-Cutrone, J. F.; Huang, S.; Shu, Y. Z.; Vyas, D.; Fairchild, C.; Menendez, A.; Krampitz, K.; Dalterio, R.; Klohr, S. E.; Gao, Q., J. Am. Chem. Soc 2002, 124, 14556-14557; Martinez-Luis, S.; Rodriguez, R.; Acevedo, L.; Gonzalez, M. C.; Lira-Rocha, A.; Mata, R., Tetrahedron 2006, 62 (8), 1817-1822; Williams, R. M.; Stocking, E. M.; Sanz-Cervera, J. F., Top. Curr. Chem., 2000, 209, 97-173. Impressive structural diversity is observed across the alkaloid family, although all members share a [2.2.2]-diazabicyclic core.
In addition to potent bioactivity and remarkable chemical structure, there are engaging biosynthetic questions regarding the origin of the [2.2.2]-diazabicyclic structural motif. The functionality is putatively derived from a biogenic intramolecular hetero-Diels-Alder cycloaddition (Williams, R. M.; Stocking, E. M.; Sanz-Cervera, J. F., Biosynthesis of prenylated alkaloids derived from tryptophan. In Biosynthesis: Aromatic Polyketides, Isoprenoids, Alkaloids, Springer-Verlag Berlin: Berlin, 2000; Vol. 209, pp 97-173). Alkaloids within this family have attracted significant attention from the synthetic community. In the context of total synthesis, five general synthetic strategies have been successfully employed to prepare the [2.2.2]-diazabicyclic core (see review of synthetic approaches from Miller, K. A.; Williams, R. M. Chem. Soc. Rev. 2009, 38, 3160-3174): (1) biomimetic Diels-Alder cycloaddition (Williams, R. M. Chem. Pharm. Bull. 2002, 50, 711-740; Williams, R. M.; Cox, R. J. Acc. Chem. Res. 2003, 36, 127-139; Jin, S.; Wessig, P.; Liebscher. J. J. Org. Chem. 2001, 66, 3984-3997), (2) radical cyclization (Herzon, S. B.; Myers, A. G. J. Am. Chem. Soc. 2005, 127 (15), 5342-5344; Crick, P. J.; Simpkins, N. S.; Highton, A. Org. Lett. 2011, 13, 6472-6475; Simpkins, N.; Pavlakos, I.; Male, L. Chem. Commun. 2012, 48, 1958-1960), (3) oxidative enolate coupling (Baran, P. S.; Hafensteiner, B. D.; Ambhaikar, N. B.; Guerrero, C. A.; Gallagher, J. D., J. Am. Chem. Soc. 2006, 128, 8678-8693), (4) SN2′ enolate alkylation (Williams, R. M.; Glinka, T.; Kwast, E. J. Am. Chem. Soc. 1988, 110, 5927-5929; Cushing, T. D.; Sanz-Cervera, J. F.; Williams, R. M. J. Am. Chem. Soc., 1993, 115, 9323-9324; Artman, G. D.; Grubbs, A. W.; Williams, R. M. J. Am. Chem. Soc., 2007, 129, 6336-6342) and (5) cation-olefin cyclization (Frebault, F. C.; Simpkins, N. S. Tetrahedron 2010, 66, 6585-6596; Frebault, F.; Simpkins, N. S.; Fenwick, A. J. Am. Chem. Soc. 2009, 131, 4214-4215).
The biomimetic Diels-Alder approach provides one of the most efficient entries to the [2.2.2]-diazabicyclic core. In the laboratory, the biomimetic Diels-Alder reaction often suffers from limited stereoselectivity. For example, in the key step of the elegant synthesis of stephacidin A (5) by Williams and co-workers (Greshock, T. J.; Williams, R. M. Org. Lett. 2007, 9, 4255-4258), prestephacidin reacts via intramolecular Diels-Alder cycloaddition to afford diastereomeric [2.2.2]-bicyclic products in a 2.1:1 diastereomeric ratio. This modest diastereomeric ratio has been consistent with other related biomimetic Diels-Alder cycloadditions.
There is a need in the art for an efficient, stereoselective entry to the [2.2.2]-diazabicyclic core.